The development of drug delivery devices for implantation into a pre-selected locus in mammals has been extensively studied. To date, a variety of surgically implantable drug delivery devices have been developed and patented, and are discussed below.
U.S. Pat. Nos. 6,217,895; 6,001,386; 5,902,598; and 5,836,935, Ashton et al. describe a surgically implantable device for local deliver of low solubility therapeutic agents in an internal portion of the body. The device comprises an inner core containing the drug isolated from the surrounding environment by a permeable coating polymer which controls the release rate of the drug. The device delivers the drug in a multidirectional way from the implantation site, exposing all the structures in the site to the delivered agent. Moreover, the drug release occurs and is through a complex technology of a coating polymer that is non-bioerodible and permeable to the drug.
U.S. Pat. No. 4,378,016, to Loeb, describes a surgically implantable device for delivering an active factor to a mammalian site. The device comprises a fluid permeable membranous sack for implantation within the mammal and an impermeable hollow tube having one end connected to an opening in the sack and the other end designed to remain outside the body of the mammal. The tube provides an access passageway to the membranous sack, such that after the sack has been surgically implanted into the mammal, a cell-containing envelope may be introduced into the sack via the tube. Upon insertion of the cell-containing envelope into the sack the cells may produce an active factor which subsequently may diffuse into the surrounding tissue or organ of the recipient.
U.S. Pat. No. 5,182,111, to Aebischer et al., describes a surgically implantable device for delivering an active factor to a pre-selected site, for example, a tissue or organ in a mammal. The device comprises a semi-permeable membrane enclosing at least one cell type that produces a specific active-factor and a second cell type that produces an augmentory factor. The augmenting factor produced by the second cell type subsequently induces the first cell type to produce the active-factor.
U.S. Pat. No. 4,479,796, to Kallok, describes a surgically implantable dispenser for infusing a pre-selected drug directly into the blood stream. Briefly, the dispenser is surgically spliced in line with a blood vessel. The dispenser encloses a replaceable cartridge of cells, micro-organisms, which produce and secrete the drug into blood flowing past the cartridge.
U.S. Pat. No. 4,309,776, to Berguer, describes an intravascular drug delivery device having a chamber containing transplanted cells for surgical implantation into the wall of a blood vessel. The device comprises a porous wall that permits a hormone produced by the transplanted cells to diffuse out of the chamber and into the blood stream U.S. Pat. Nos. 6,251,090; 5,830,173 and 5,725,493, to Avery et al., describe a drug delivery device, comprising a refillable reservoir connected to the vitreous cavity through a tube. This concept requires intraocular invasion, which limits its application to situations when the integrity of the targeted tissue is not an issue.
U.S. Pat. Nos. 6,416,777 and 6,413,540 disclose a device that once positioned underneath the Tenon's capsule, in contact to the sclera, is supposed to deliver agents to the eye. Such system is composed of an outer layer impermeable to the delivered therapeutic agent, diminishing its wash out by the periocular fluids. The device has a geometry that facilitates its insertion and placement in the sub-Tenon's space, and reference is made to a method to place and hold it under the inferior oblique muscle, avoiding its dislocation from its original location and proportioning its positioning near the macula area. No references are made to methods to hermetically seal it to the sclera or to the targeted tissue. Moreover, the design of those devices does not accommodate methods to carry more than one agent, as in a bi-compartmental reservoir neither it refers to refilling ports to allow reposition of the liquid therapeutic agents.
The necessity of the use of a hermetically sealed device arises from characteristics determined by the drugs and tissues. Among the drug-related factors are: narrow difference in the efficacious-toxic concentration; high instability or susceptibility to inactivation before reaching the aimed tissue; the requirement of prolonged and steady release curves, particularly in chronic diseases; and availability in liquid or gel state. The tissue factors are mainly related to the level of topographic specificity that is required from that agent, and not less importantly to the harms and susceptibility of the surrounding tissues to the drug toxic effects.
The possibility of drug leakage through the device-tissue junction sharply excludes the use of some important therapeutic agents, not only cytotoxic drugs, but other more specific agents. Angiogenic peptides could never be applied and exposed to other tissues other than where aimed to act. If aimed to the choroid by increasing the blood flow and stimulating capillary growth, its possible exposure to the vascularized periocular tissue before even crossing the sclera, beyond dissipating the angiogenic effect, could increase the flux of blood and plasma around the implant and speed up the degradation or neutralization of its active agent. Moreover, biological processes occurring in that location may alter significantly the release pattern of any agent from the delivery device whether the agent is still active or not.
Inflammatory reactions are the basis of the healing process in mammalians, involving the release of a wide range of chemical, biological and cellular factors that ultimately lead to a reorganization of the tissue. Scar formation and foreign body reactions are common responses from an organism to traumatic and surgical injuries, particularly if there is exposure to inert or immunogenic materials. These responses are created to reconstitute the affected or exposed tissue through a series of reactions that frequently culminate with strengthening of the affected tissue and isolation or extrusion of the foreign body.
Over the past decades significant experience with periocular implants has been achieved through the well established practice of encircling elements for treating retinal detachment and by the proliferation of filtration devices for the surgical therapy of glaucoma. Many polymers were tested for that purpose and the experience accumulated over the years showed that the encapsulation of the implant invariably happens after periocular implantation. Indeed, even for largely used medical products such as silicone, it was shown that the encapsulation process starts as soon as 3 days following insertion. Nevertheless, a fibrotic reaction to a prosthesis or to a structural implant is not so harmful. Instead, it is even desired to provide mechanical stability to the implant and enhance its structural function19,20,21,22.
The lack of a way to hermetically seal the device to the tissue would not only affect the way the carried agent would act and react with the surrounding tissues, but also the way the surrounding tissues would respond to the agent and the system. The encapsulation of such system, and the formation of a layer of scar tissue between the drug reservoir and the organ surface would change significantly the pattern of drug release altering the main determinants of diffusion through that surface, which is primarily composed by a membrane with known characteristics, and diffusion coefficients for certain molecules.
In Ophthalmology, several studies were carried out to characterize the sclera, the most external layer of the eyeball, as a membrane. Many experiments justified the use of periocular injections to deliver drugs to the eye. Edelhauser et al. studied extensively the properties of the sclera as a permeable membrane. His in vitro studies were further enhanced by in vivo studies to show how periocular injections can deliver agents to the internal eye tissues. It was shown that molecules as large as 70 KDa can diffuse across the sclera and reach the intraocular space, even against a pressure gradient. Such properties are partially explained by porous characteristics of the scleral collagen, although the whole mechanism is still not totally understood, particularly the mechanisms these large molecules can reach the intravitreal space, bypassing tight junctions of very selective barriers such as the outer blood-retinal barrier. Indeed, the unprotected transcleral route has been used for many years and has proved to be effective with the administration of certain drugs. Anti-inflammatory steroids are injected through the conjuctiva into the subTenon space and put directly in contact with the sclera, which allows the diffusion of the drug toward the intraocular space, providing high therapeutic levels of the drug to the various layers of the eye. Deposit formulas of steroids are available with demonstrated safety and equivalency, or superior effectiveness to the systemic route, but without its inconvenient side effects. However, because these injections are unprotected from the surrounding orbital tissue, much of the injected dose is absorbed systemically and carried away from the site. The therapeutic effect is short-lived7,8,9.
Some other drugs cannot be administered by this periocular route because of significant irritation and toxicity to the adjacent tissues at the high levels necessary to permeate the layers of the eye. High concentrations of agents are necessary because of dissipation of the drug in the periocular tissue. This is mainly attributed to a washout mechanism by the periocular soft tissue or inactivation of the agents by inflammatory cells, immunoglobulins and plasma components before they reach the targeted structure.
In certain conditions, such as in endophthamitis, the intraocular use of the drug is appropriate by providing high levels of the antibiotic available in a short period of time. However, for chronic use, repeated intraocular injections bring an unnecessary high risk of complications, either from the injection procedure or from high drug concentrations instantaneously provided by the direct injection. Intraocular procedures are not always possible. Inflammatory conditions such as uveitis, particularly in the severe disorders, such as in Behcet's disease, even minimally invasive intraocular procedures can lead to a severe and prolonged hypotony. Intraocular cancers also require non-invasive approaches due to the risk of cancer cells being disseminated throughout the orbit. Retinoblastoma, most common primary intraocular tumor in childhood, is an ideal disorder for the local delivery of chemotherapeutics. One of its clinical presentations, characterized by seeding of tumor cells in the vitreous gel, is currently treated by systemic chemotherapy. The failure of systemic treatment is frequently due to limited achievement of therapeutic levels of the drugs in that location, and often leads to removal of the eye. Administering the drug directly into the vitreous is impossible because of the risk of tumor cell dissemination, directly leading to death.
Regional therapy is an alternative and is currently under clinical trials. Promising efficacy has been achieved but some toxic side effects were reported as well. In this specific situation high levels of cytotoxic drugs, such as carboplatin in the orbit, can result in unpredictable side effects during the patient's lifetime, particularly in the retinoblastoma population which is more susceptible to secondary neoplasias due to gene mutations. Similar therapeutic levels of the drug in the eye could be achieved if the periocularly injected drug was isolated or protected from the extraocular connective tissue, which offers potential advantages of prolonged release time and certainly fewer side effects to the orbital structures and optic nerve. Furthermore, a controlled release of those agents could be achieved since the interface area with the drug is well defined, a main predictor of drug diffusion rates across the sclera. The positioning of the drug in contact with a specific area of the sclera would also avoid exposure of more sensitive structures, e.g. optic nerve, to potentially toxic drugs at high concentrations.
Regional therapy has been extensively studied and has proved to be efficacious in several conditions. Although drug delivery systems based on polymer technology have improved the bioavailability and pharmacokinetics of therapeutic agents in the targeted sites, lack of local specificity is still a major limitation to its clinical applicability.
New classes of therapeutic agents have demonstrated promise, but the inability to efficiently and specifically deliver such agents to the target limited the achievement of successful results to the in vitro studies. A number of those when tested in vivo, fail to produce the same results as in vitro.
Moreover, tumor cells as well as infectious agents can spread to other organs or even systemically, once the natural barriers of the organ are surgically broken. The systems aforementioned, when not delivering the agent directly to the interstice of the aimed tissue, can still provide therapeutic levels by releasing the agent to the cavity or the surrounding space and fluids. This ultimately can lead to uptake from the organ and from any of the adjacent structures. Such perfusion systems lack specificity and are not suitable for clinical use when the drugs are toxic to the surrounding structures. This problem becomes more prominent when the agent may trigger other pathologic processes. This is more frequent when using viral gene vectors, inhibitors of biological factors and non-specific sensitizers.
Patched delivery systems have been developed for transdermal or transmucosal release of drugs. Such systems are designed to have one interface with the dermal or mucosal epithelium through which the diffusion of drug occurs. The other interface is usually external of the target body tissue, e.g. the external environment in the case of a transdermal patch, or the intestinal lumen or oral cavity, in transmucosal models. The main concern in designing those devices is to protect the carried agent from the secretions of the gastrointestinal, oral and nasal tracts and consequently to allow more drug to reach the systemic circulation, instead of directly acting in a targeted organ or tissue1,2,3.
With transmucosal devices any release from the external surface will be neutralized by luminal enzymes, flora or physical inactivation, or will reach the systemic circulation after distal absorption what is ultimately the goal of most of these drug delivery systems. Neither transdermal or transmucosal delivery systems were conceptualized to be surgically implanted nor designed to meet the level of biocompatibility necessary to be exposed to internal body fluids, e.g. blood, connective tissue, or any internal cellular response. Their application is under exposure to body secretions, therefore, they are not usually subject to severe inflammatory reactions and do not require high levels of biocompatibility, factors that make them unsuitable for surgical implantation1,2.
Systems like polymer shields for drug release as the ones available for ocular use, share some of the characteristics of the transdermal and transmucosal systems. They do not aim to deliver the drug directly to the cornea or conjunctiva or to any specific ocular structure, but release the agent to a body secretion fluid as the the lacrimal film, in a multidirectional way. From the tear film agent diffusion occurs throughout the ocular surface and later to the lacrimal drainage system and nasopharyngeal mucosa, again exposing other tissues to side toxic effects. These systems can provide a sustained release of an agent, but in a non-selective way, dissipating its effects to all the surrounding structures, e.g. conjunctiva, lid skin, cornea, lacrimal system. As with the transdermal and transmucosal systems, those systems were designed to offer the advantage of non-invasive sustained release, not be implanted through surgical procedures, but just attachment to body or mucosal surfaces.4,5 
Experimental and clinical evidences suggest that organ surfaces exposed to high levels of drugs can lead to internal therapeutic levels even higher than those achieved by systemic administration. The potential diffusion properties of organs and tissues are discussed, as well as the advantages of its exploration as a therapeutic route.
Bioactive peptides are agents necessary and naturally present in biological process, but may also be undesirably present in pathogenic situations, e.g. tumors, choroidal neovascular membranes, and absent as well, e.g. ischemic areas of the myocardium. The over or down regulation of such factors can lead to the improvement of pathologic conditions, and their efficient use as therapeutic agents, require the ability to provide to the target tissue the desired quantity in a sustained and prolonged fashion. The same protected regulated delivery is required for gene vectors, antisense agents, antibiotics, cytotoxic drugs, enzymes, certain hormones, etc. Other agents known as sensitizers also require a specific action, and the drug uptake by the targeted tissue will later define the efficiency of the definitive treatment, e.g. chemo, laser, radio or thermal therapies, in restricting and enhancing its effects, as well as side effects, to that site.
Local drug delivery is also under clinical studies for the treatment of intracranial tumors. Some neural origin tumors, such as malignant glioma have received most of the attention. These tumors are treated by a standard combination of surgical resection and external beam radiation. Due to the ability of this tumor to invade the normal adjacent brain it often recurs in the adjacent margins of resection. Based on those characteristics and the tumor unresponsiveness to systemic chemotherapy, the local delivery of drugs, sensitizers and peptide vectors started to be considered and studied as a treatment option, with potential effects on the quality of life of affected subjects.
Brem et al. have reported prolonged survival using polymers containing BCNU in controlled trial for recurrent glioblastoma. Such polymers are prepared to release 50% of the drug in the first 24 hours, and 95% by 120 hours10,11.
Another study reported a high incidence of perioperative complications, such as wound infection and seizures, without showing advantages over the conventional treatment12. Exposing tissues to higher concentrations of a therapeutic agent increases the chance of a greater efficacy without systemic side effects, but also increases the risk of local side effects, usually dose-related.
The prior art did not recognize that a selective and protected local delivery system could substantially improve the effectiveness of the treatment, as well as make available other agents never accepted for that use because of potential toxicity to the adjacent structures, and prior art systems designed to deliver drugs to the site where they are implanted provide no protection for other sensitive normal structures nearby.
For example, regional therapy to deliver bioactive agent to the myocardium and epicardial space has been extensively explored. Pericardial effusion syndrome and metastatic tumors were shown to respond very well to local delivery of chemotherapeutics by intrapericardial perfusion of 5-Fluorouracil and cisplatin through a catheter. This technique is efficacious in providing the epicardium space with high levels of drug, but imposes the risk of secondary infection if used in a chronic basis.13,14 
An elegant study by Darsinos et al. showed the pharmacokinetics of digoxin and lidocain in the various heart tissues, including valves. Their study showed that these compounds follow an irregular distribution among cardiac tissues, after pericardium injection. Again, specificity of an agent to a determined region of the same organ is desirable for conditions such arrythmias and dysfunctional cardiopathies. Absorption of digoxin by the atria and absorption of both drugs by intrapericardial aorta were higher than that of other heart tissues, between 20 and 60 minutes. At 30 and 60 minutes, lidocaine was evenly distributed across the LV wall while digoxin 50 micrograms was mainly concentrated subepicardially. This distribution limits the intrapericardial route for administering those agents to situations where higher levels in those areas are desired15. The same author showed in another study that the concentration of amiodarone injected into the pericardium was higher in the subepicardium compared to deeper layers of the left ventricule, without measurable concentration in the blood16. The preferential distribution of those agents is due to an increased uptake of the drug by certain areas. Since this injection exposes the whole area of the myocardium surface to the agent, it is susceptible to different uptake rates between regions, and consequently to a non-controlled preferential delivery.
The effectiveness of bioactive agents as therapeutics depends on their delivery routes. For some bioactive reagents, their natural biological occurrence make them subject to inactivation or saturation by a variety of factors normally present in fluids and tissues before they reach their targets. Some growth factors and other compounds were shown to increase the vascularization of infarcted areas of the myocardium. Uchida et al. showed in a dog model of myocardial infarction, that the transcatheter intrapericardial injection of basic Fibroblast Growth Factor (bFGF) plus heparin sulfate is effective in causing angiogenesis and myocardial salvage more in the subepicardial infarcted area than in the subendocardial area. Further studies done in porcine model of chronic myocardial infaction confirmed the effectiveness of intrapericardial injection of b-FGF in inducing vascularization of myocardium.17,18. Although this shows promising results in animal studies, it is still questionable whether this route will be feasible in patients with prior instrumentation, including bypass surgeries.
The intravenous route was also considered and clinically studied, but did not show benefits compared to placebo. The use of this delivery route imposes concerns about a potential acceleration of retinal vascular diseases and occult neoplasias.
Vascular growth factors tend to bind to their receptors or be inactivated, so they are subject to saturation before reaching deeper layers of the tissues. Consequently, if vascular growth factors are unequally distributed among different layers of the tissue, their effects are expected to be as well. To allow them to reach deeper layers of the myocardium, it is necessary to protect them from unaffected areas, and limit their action to a defined pathologic area, where they will have a better chance to reach deeper after a longer period of exposure. A method for delivering the agent in a localized, sustained, protected and very selective manner, would more likely perform those tasks, with less side effects, through a minimally invasive implantation procedure, potentially benefiting a significant affected population that is not eligible for more morbid procedures. This strategy offers the advantages of the intrapericardial procedures, with comparable efficacy to intramyocardial approaches.
The use of bioactive agents locally has been subject to a number of studies. Inhibitors of vasculogenesis are potential tools for treating angioproliferative eye diseases such as retinopathy of prematurity and age-related macular degeneration, two leading causes of blindness in premature newborns and the elderly population.